title: Identification of a developmentally regulated pathway of membrane retrieval in neuronal growth cones.
abstract: The growth-cone plasma membrane constantly reconfigures during axon navigation and upon target recognition. The identity and regulation of the membrane pathway(s) participating in remodeling of the growth-cone surface remain elusive. Here, we identify a constitutive, high-capacity plasma-membrane-recycling activity in the axonal growth cones, which is mediated by a novel bulk endocytic pathway that is mechanistically related to macropinocytosis. This pathway generates large compartments at sites of intense actin-based membrane ruffling through the actions of phosphatidylinositol 3-kinase, the small GTPase Rac1 and the pinocytic chaperone Pincher. At early developmental stages, bulk endocytosis is the primary endocytic pathway for rapid retrieval of the growth-cone plasma membrane. At later stages, during the onset of synaptogenesis, an intrinsic program of maturation leads to downregulation of basal bulk endocytosis and the emergence of depolarization-induced synaptic-vesicle exo-endocytosis. We propose that the control of bulk membrane retrieval contributes to the homeostatic regulation of the axonal plasma membrane and to growth-cone remodeling during axonal outgrowth. In addition, we suggest that the downregulation of bulk endocytosis during synaptogenesis might contribute to the preservation of synaptic-vesicle specificity.
authors.affiliation: S. Raffaele Scientific Institute/Vita-Salute University and IIT Unit of Molecular Neuroscience, 20132 Milano, Italy.
authors.forename: Dario
authors.initials: D
authors.lastname: Bonanomi
authors.forename: Eugenio F
authors.initials: EF
authors.lastname: Fornasiero
authors.forename: Gregorio
authors.initials: G
authors.lastname: Valdez
authors.forename: Simon
authors.initials: S
authors.lastname: Halegoua
authors.forename: Fabio
authors.initials: F
authors.lastname: Benfenati
authors.forename: Andrea
authors.initials: A
authors.lastname: Menegon
authors.forename: Flavia
authors.initials: F
authors.lastname: Valtorta
mesh_terms: D000818:Animals; D002462:Cell Membrane / Q000378:metabolism*; D002478:Cells, Cultured; D004705:Endocytosis; D020439:Growth Cones / Q000378:metabolism*; D006624:Hippocampus / Q000166:cytology / Q000254:growth & development* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D055495:Neurogenesis; D009474:Neurons / Q000166:cytology* / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D013572:Synaptic Vesicles / Q000378:metabolism